Microglia, the immune cells of the central nervous system, undertake a number of different functional roles. One major role consists of participating in a signaling pathway that leads to excitatory neuronal death in acute (e.g., stroke), or chronic (e.g., Alzheimer's, amyotrophic lateral sclerosis, glaucoma) neurodegenerative diseases. We propose to investigate the process of microglial activation in this setting of excitotoxic neurodegeneration. Identification and characterization of genes involved in microglial activation could generate potential targets in the CNS for the rational design of new therapeutic approaches for intervention in these diseases. We propose to define, using DNA chip technology, the signaling cascades that result in microglial activation. Furthermore, we will make use of tissue plasminogen activator (tPA), a serine protease that is produced by neurons and microglia and that mediates microglial activation via interaction with a microglial cell surface receptor, annexin II. tPA will be used as a tool to dissect the process of activation, since it functions as an extracellular trigger to activate intracellular effectors. The signaling pathways that lead to microglial activation will be analyzed. This set of experiments will identify candidate targets for subsequent pharmaceutical study for inhibition or suppression of the neurotoxic properties of activated microglia.